The Geriatric Depression Scale (GDS) is a widely used instrument to assess depression in older adults. The short GDS versions that have four (GDS-4) and five items (GDS-5) represent alternatives for depression screening in limited-resource settings. However, their accuracy remains uncertain.To assess the accuracy of the GDS-4 and GDS-5 versions for depression screening in older adults.Until May 2020, we systematically searched PubMed, PsycINFO, Scopus, and Google Scholar; for studies that have assessed the sensitivity and specificity of GDS-4 and GDS-5 for depression screening in older adults. We conducted meta-analyses of the sensitivity and specificity of those studies that used the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10) as reference standard. Study quality was assessed with the QUADAS-2 tool. We performed bivariate random-effects meta-analyses to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI) at each reported common cut-off. For the overall meta-analyses, we evaluated each GDS-4 version or GDS-5 version separately by each cut-off, and for investigations of heterogeneity, we assessed altogether across similar GDS versions by each cut-off. Also, we assessed the certainty of evidence using the GRADE methodology.Twenty-three studies were included and meta-analyzed, assessing eleven different GDS versions. The number of participants included was 5048. When including all versions together, at a cut-off 2, GDS-4 had a pooled sensitivity of 0.77 (95% CI: 0.70–0.82) and a pooled specificity of 0.75 (0.68–0.81); while GDS-5 had a pooled sensitivity of 0.85 (0.80–0.90) and a pooled specificity of 0.75 (0.69–0.81). We found results for more than one GDS-4 version at cut-off points 1, 2, and 3; and for more than one GDS-5 version at cut-off points 1, 2, 3, and 4. Mostly, significant subgroup differences at different test thresholds across versions were found. The accuracy of the different GDS-4 and GDS-5 versions showed a high heterogeneity. There was high risk of bias in the index test domain. Also, the certainty of the evidence was low or very low for most of the GDS versions.We found several GDS-4 and GDS-5 versions that showed great heterogeneity in estimates of sensitivity and specificity, mostly with a low or very low certainty of the evidence. Altogether, our results indicate the need for more well-designed studies that compare different GDS versions. Depression is a major global public health issue . Older aIn older adults, depression´s somatic symptoms are similar to other chronic health conditions , and mooIts full version contains 30 questions (GDS-30) and requires substantial time for assessment. Therefore, shorter GDS versions, selecting some of the GDS-30 items ,13, haveThe accuracy of these GDS-4 and GDS-5 versions remains unclear . AlthougWe conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines . The stuThe inclusion criteria were as follows: 1) Observational studies that reported the sensitivity and specificity of any of the GDS-4 and GDS-5 versions for the diagnosis of depression, using the DSM or ICD-10 diagnosis criteria as reference standard, since these provide a commonly used and accepted framework for depression diagnosis in the clinical practice , 2) studWe systematically searched the following databases and search engines: PubMed, PsycINFO and Scopus until April 24, 2020. Additionally, we searched the first 100 results retrieved in Google Scholar up to May 16, 2020. Google Scholar was searched to identify grey literature through the first 100 records, as systematic reviews usually examine the first 100 records in Google Scholar –32 becauInitially, we removed all duplicated records by using the EndNote software. Two independent authors (ANF and DRSM) independently screened all results for inclusion, first reviewing the titles and abstracts, and later performing a full-text assessment, trough EndNote software. Any disagreement during the selection process was discussed with a third party (ABC) and resolved by consensus.Two authors (ANF and BSC) independently performed the data extraction from each included study using a standardized Microsoft Excel sheet. Differences were solved by a third researcher (ABC). The following variables were extracted: first author, year of publication, country, population characteristics , inclusion and exclusion criteria, prevalence of depression in the study according to the reference standard, funding, intervention , reference standard , type of depression evaluated, and numerical results of sensitivity and specificity. When there were doubts about any information reported in the studies, we sent emails to the authors to clarify the information.Two researchers (DRSM and MEDB) independently assessed the risk of bias of the included studies using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool . This toAdditionally, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to report the certainty on the evidence ,42. RiskWe conducted meta-analyses of the sensitivity and specificity of each of the GDS-4 and GDS-5 versions whenever studies fulfilled the following condition: 1) There was more than one study that compared the same version of GDS-4 or GDS-5 at the same cut-off point. We performed the meta-analyses of GDS-4 and GDS-5 separately.When there were at least four studies to include in the meta-analysis, we used bivariate mixed-effects models via random effects that consider the correlation between sensitivity and specificity by each study to provide estimates of effects . When leIn addition, we meta-analyzed altogether the results of the included studies that assessed the same cut-off point of any GDS-4 version. Likewise, we meta-analyzed altogether the results of the included studies that assessed the same cut-off point of any GDS-5 version.Heterogeneity was assessed through visual assessment of forest plots. To assess if there were subgroup differences across different GDS versions, also we evaluated heterogeneity through visual assessment of forest plots. All analyses were performed using the Stata v14.0 software.Overall, 2,740 records were retrieved in the database systematic search. After removal of duplicates, 2,254 records were screened, and 71 records were full-text reviewed. From these, we excluded 52 records for not fulfilling the inclusion criteria. Reasons for exclusion are explained in Additionally, we identified seven records that meet our inclusion criteria after searching the lists of references of all included studies, the lists of references of previous reviews, and the lists of articles that cited each of the included studies (through Google Scholar). For a total of 26 included records.Of these, some presented results from the same study: Allgaier 2011 and Allgaier 2013, Castelo 2007 and Castelo 2010, and Cheng 2004 and Cheng 2005 –47. ThusThe number of participants included was 5048. Individual studies´ participants ranged from 60 to 586. Regarding the population, one study was performed only in people without dementia –47,49–61Regarding the short GDS versions, 11 studies only assessed the GDS-4 ,52,57,60Each of the GDS-4 and GDS-5 versions assessed different combinations of GDS-30 items. The list of the items assessed by each version is detailed in Using the QUADAS-2 tool, we found a high risk of bias in most of the studies. There was high risk of bias in the index test domain. Specifically, the question about the lack of pre-specification of the cut-off points used was the most common flaw .As stated before, we assessed the sensitivity and specificity of studies that used the DSM or ICD-10 diagnosis criteria as a reference standard, for all GDS-4 and GDS-5 versions. Thus, 23 studies were included in these quantitative analyses.For the GDS-4 assessment, 14 studies with a total of 3266 participants were included. We obtained eleven sensitivity and specificity estimates, which gave information regarding six versions of GDS-4 at different cut-offs: D’Ath at cut-off 1 and 2; Van Marwijk at cut-off 1, 2 and 3; Cheng at cut-off 1, 2, 3 and 4; Martinez at cut-off 2; and Galaria at cut-off 2 .When taken together, GDS-4 versions at cut-off 1 had a pooled sensitivity of 0.90 (95% CI: 0.85–0.93) and a pooled specificity of 0.57 (95% CI: 0.45–0.67), at cut-off 2 had a pooled sensitivity of 0.77 (95% CI: 0.70–0.82) and a pooled specificity of 0.75 (95% CI: 0.68–0.81), and at cut-off 3 had a pooled sensitivity of 0.63 (95% CI: 0.53–0.71) and a pooled specificity of 0.78 (95% CI: 0.69–0.84).Among the GDS-4 versions, the results for those with the lower cut-off point tend to have a higher sensitivity and a lower specificity. When assessing the sensitivity and specificity estimates, the Galaria at cut-off 2 and the Cheng at cut-off 4 had the greatest balance, the first one favoring the sensitivity and the second one the specificity.We assessed and found differences in sensitivity and specificity estimates for the different GDS-4 versions, at each cut-off point used.For the GDS-5 assessment, 15 studies with a total of 3085 participants were included. We obtained thirteen sensitivity and specificity estimates, which gave information regarding five versions of GDS-5 at different cut-offs: De Dios or Ortega at cut-off 2, Hoyl at cut-off 1, 2 and 3, Martinez at cut-off 2, Apostolo at cut-off 1, 3, 4 and 5, and Heisel or Cheng at cut-offs 1, 2, 3 and 4 .When taken together, GDS-5 versions at cut-off 1 had a pooled sensitivity of 0.89 (95% CI 0.83–0.94) and a pooled specificity of 0.41 (95% CI 0.30–0.53), at cut-off 2 had a pooled sensitivity of 0.85 (95% CI: 0.80–0.90) and a pooled specificity of 0.75 (95% CI: 0.69–0.81), at cut-off 3 had a pooled sensitivity of 0.60 (95% CI 0.50–0.68) and a pooled specificity of 0.83 (95% CI 0.74–0.89), and at cut-off 4 had a pooled sensitivity of 0.44 (95% CI 0.35–0.53) and a pooled specificity of 0.94 (95% CI 0.88–1.00).Among the GDS-5 versions, the results for those with the lower cut-off point tend to have a higher sensitivity and a lower specificity. When assessing the sensitivity and specificity estimates, the De Dios or Ortega at cut-off 2 had the greatest balance of sensitivity  and specificity .We assessed and found differences in sensitivity and specificity estimates for the different GDS-5 versions, at each cut-off point used.A summary of the sensitivity analysis and all the forest plots could be found in We used GRADE summary of findings (SoF) tables to report the certainty of evidence . OverallThe first versions of the GDS-4 and GDS-5 were D’Ath and Hoyl versions, respectively ,15. HowePrevious systematic reviews have assessed the accuracy of these GDS short versions ,25–27. TAll previous meta-analysis had pooled the results from studies using different GDS versions. However, results suggest that different versions have different sensitivity and specificity estimates for the same cut-off point.Among the assessed GDS-4 versions, the balance between sensitivity and specificity was greater for the Galaria version at cut-off 2 , and for the Cheng version at cut-off 4 . Among the assessed GDS-5 versions, the balance between sensitivity and specificity was greater for the “De Dios or Ortega” version at cut-off 2 . Although this suggests that the “De Dios or Ortega” version at cut-off 2 may be a balanced option, with a high certainty that allows a more confident estimation of underdiagnosis and overdiagnosis rates, decision-makers must also consider other factors such as applicability in their contexts or cultural variations in the manifestation of depression, before deciding which GDS version to use.Subgroup analyses found that estimates were different across different GDS-4 versions, and across different GDS-5 versions. While this suggests that some versions may have a better performance than others, the low certainty of these estimates prevents from making any solid conclusion. However, it seems sensible that future systematic reviews evaluate each version separately.Moreover, most of the meta-analyses for each version also had significant heterogeneity, which may be due to differences in risk of bias, populations characteristics , study setting, or reference standard usage . Moreover, some cultural differences in the construct of depression may cause heterogeneous results across different contexts . RegretfCertain limitations must be considered when interpreting the results: 1) certainty of the evidence was low or very low for most of the results, mainly due to heterogeneity and risk of bias. 2) Most of studies had a high risk of bias, mainly due to the selective reporting of the cut-off points (some studies seemed to report only the cut-off with the highest sensitivity and specificity), and the assessment of GDS-4 or GDS-5 accuracy by extracting items assessed in a full GDS-30 interview . 3) Studies had heterogeneous settings, population characteristics, and depression definition.However, to the best of our knowledge, this is the most comprehensive systematic review performed to date regarding the accuracy of GDS-4 and GDS-5, which included 23 studies; and is the first systematic review that provides the pooled estimates of each GDS-4 and GDS-5 versions. Thus, our results would help guide clinical practice and clinical guidelines recommendations.This study summarizes the sensitivity and specificity of GDS-4 and GDS-5 for depression screening in older adults. We found several GDS-4 and GDS-5 versions, the results of which had great heterogeneity, which suggest that some versions may be more accurate than others. Certainty for the evidence was low or very low for almost all estimates. Altogether, our results indicate the need for more well-designed studies that compare different GDS versions.S1 Checklist(DOC)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 Fig(DOCX)Click here for additional data file.S5 Fig(DOCX)Click here for additional data file.S6 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 File(XLSX)Click here for additional data file.S1 Database(XLSX)Click here for additional data file. 22 Mar 2021PONE-D-21-03547Accuracy of the Geriatric Depression Scale (GDS)-4 and GDS-5 for the screening of depression among older adults: a systematic review and meta-analysisPLOS ONEDear Alvaro Taype-Rondan, Thank you for submitting your manuscript to PLOS ONE. 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The PLOS ONE style templates can be found athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf2. Please include a copy of Table 4 which you refer to in your text on page 13.http://journals.plos.org/plosone/s/supporting-information.3. Please include captions for *all* Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Partly**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: No**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: Overall, the authors have done rigorous work to examine the utility of the brief versions of GDS (GDS-5 and 4) in screening for geriatric depression. Despite the challenge of inconsistency in the item used and the cut-off value, they managed to segregate the various versions of GDS4 and 5 with the same cut-off point and performed meta-analysis whenever possible. The outcome is summarized as pooled sensitivity and specificity with the Youden index. Since2*2 contingency table is constructed it would be more informative if the authors could report other measures of diagnostic accuracy like a pooled estimate of the positive and negative likelihood ratios, summary diagnostic odds ratio and area under curve (AOC).Major:Methods: For the outcome measures, since 2 by 2 contingency table is constructed, it would be better if authors could include other measures of diagnostic accuracy like a pooled estimate of the positive and negative likelihood ratios, summary diagnostic odds ratio, and area under curve (AOC).Furthermore, I wonder if Cronbach’s alfa of the items enlisted in table 2 could be summarized to recommend for future studies.Minor:Line 60: it is combining? Or just selecting some items from the original 30-item version?Line 62,63: word different and altogether may not be needed.Line 147: Regarding the population, …. The sentence needs reconstruction. Only one study excluded the sample with dementia.Line 74-81: Authors have elaborated the various eligibility criteria for inclusion. Authors can further clarify:1.      Language of the tool. If translated, whether the translation was done appropriately2.      I understood that irrespective of Study design, setting, the way the interview was included. It may be better to mention.Reviewer #2: This review aims to assess the diagnostic accuracy of Geriatric Depression Scale (GDS)-4 and GDS-5 for screening of depression among older adultsGeneral commentsThis is an interesting paper but the rationale needs to be strengthened and methods revised considerably. The methodology is presents some inaccuracies and confusion with methods used for meta-analyses of intervention reviews. I would recommend the following references to the authors;http://www.prisma-statement.org/Extensions/DTA• PRISMA for Diagnostic Test Accuracy Reviews (DTA): https://pubmed.ncbi.nlm.nih.gov/24274632/• Leeflang MM. Systematic reviews and meta-analyses of diagnostic test accuracy. Clin Microbiol Infect. 2014 Feb;20(2):105-13. doi: 10.1111/1469-0691.12474. PMID: 24274632 https://pubmed.ncbi.nlm.nih.gov/19075208/• Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM; Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med. 2008 Dec 16;149(12):889-97. doi: 10.7326/0003-4819-149-12-200812160-00008. https://methods.cochrane.org/sdt/handbook-dta-reviews• DTA meta-analyses methods: Chapter 10  of the Cochrane handbook for DTA reviews. https://gradepro.org/ GRADE Pro /GDT is a free software that enables authors conduct GRADE assessments accurately and also generates nice summary of findings tables. (Table 3 needs to follow this format)• GRADE: Specific commentsABSTRACTMethods section• This statement in the methods section is unclear. “We conducted sensitivity and specificity meta-analyses of those studies using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10). Do the authors mean using “Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10)” as the reference standard? In its current form, the statement implies that these were the statistical methods used to pool the estimates of sensitivity and specificity.• “Mostly, significant subgroup differences across versions were found”. It would be helpful to state which subgroups were measured. Do the authors means subgroup differences at different test thresholds?Conclusion• This statement in the conclusion is not qualified in the results section. “Conclusions: The accuracy of the different GDS-4 and GDS-5 versions showed a high heterogeneity”. This statement is best placed in the results section.MAIN TEXTIntroduction• The rationale, “accuracy remains unclear” is a vague rationale. Is the lack of clarity due to variation in accuracy estimates of existing primary studies? Please qualify that rationale better. I also disagree that the existing published systematic reviews are all outdated. Some were published in 2017 (ref 27) and 2019 (ref 26). These are recent reviews. An outdated review is usually > 5years.• It would be good to include a paragraph in the rationale about the best available test/reference test- what it is, its strengths and limitations as well as the anticipated role of the index tests. Are the GDS scales being evaluated as replacement tests for the reference tests/existing tests?Methods• The reporting of this review would be greatly improved if the authors were guided by the PRISMA extension for Diagnostic Test Accuracy reviews and not the original PRISMA. Please re-write this review based on PRISMA DTA.Search strategy• Please clarify why only the first 100 results yielded in google scholar were searched. Google scholar generates lots of hits. How did the authors ensure that the first 100 were the most relevant to screen?Data selection and extraction.• The authors state that duplicates were removed using endnote reference tool and data extraction was done using an excel sheet. Please clarify which platform/software specifically was used to screen titles, abstracts and full texts of the search yield?Risk of bias and certainly of evidence• Please add more detail about how GRADE was used to assess certainty of evidence? How was downgrading done?Statistical analyseshttps://methods.cochrane.org/sdt/handbook-dta-reviews• This section needs to be revised for clarity. Please refer to Chapter 10  in the Cochrane handbook for DTA reviews. • Please provide a reference to qualify the type of meta-analyses used (bivariate model).Also clarify if it was the bivariate random effects method (which is commonly used) or bivariate mixed-effects models. By mixed effects do you mean random and fixed effects combined?• Please state clearly at the beginning of this section that meta-analyses of GDS-4 and GDS-5 were done separately• Please provide a rationale why the Y index was calculated provided. This is a global measure of accuracy and to my knowledge rarely used nowadays because of its limitations.• Please revisit how heterogeneity is measured in DTA reviews. I2 is used to assess heterogeneity of intervention reviews and not recommended for DTA reviews.Results• The results section about risk of bias is thin. QUADAS has four domains against which risk of bias results are reported. Please specify which domains were deemed to have risk of bias.https://gradepro.org/).• Table 3. The reporting of GRADE results is incorrect. GRADE assessment is given for an overall summary of evidence and not individual studies as presented. QUADAS is for individual studies but GRADE summarises the overall certainly of evidence across the domains quality/risk of bias; inconsistency, imprecision, indirectness and publication bias. For example, one would except an overall certainly of evidence for pooled results at each cutoff but not for individual studies. Please refer to the GRADE pro software to help with the GRADE assessment as well as generation of an accurate summary of findings table (**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  23 Apr 2021Dear editor and reviewers,Thank you for your kind consideration. In this letter, we proceed to respond to each of the comments made by the reviewers and the journal requirements.Sincerely, Alvaro Taype-Rondan, corresponding authorJournal Requirements:1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfAnswer. Thank you for your observation. We have checked the requirements and our manuscript meets them.2. Please include a copy of Table 4 which you refer to in your text on page 13.Answer. Thank you for your observation. In our manuscript, there are 3 tables in total. "Table 4" should not appear. On page 13, we have replaced “Table 4” with “Table 3”.http://journals.plos.org/plosone/s/supporting-information.3. Please include captions for *all* Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: Answer. Thank you for your observation. We added the captions for Supporting Information files at the end of the manuscript. Also, we have updated the in-text citations.Reviewers' comments:R1.1: Methods: For the outcome measures, since 2 by 2 contingency table is constructed, it would be better if authors could include other measures of diagnostic accuracy like a pooled estimate of the positive and negative likelihood ratios, summary diagnostic odds ratio, and area under curve (AOC).Answer. Thank you for your recommendation. For decision making in clinical practice, sensitivity and specificity are used to identify false positives, false negatives, true positives, and true negatives, and thus to consider the desirable and undesirable consequences of diagnostic tests for patients (1). Although we could include the other diagnostic measures, we believe that it would enlarge the table, and make it less understandable. Thus, we chose to keep sensitivity and specificity as the most useful and sufficient indicators for decision-making.1. Buehler AM, Ascef BO, Oliveira Júnior HA, Ferri CP, Fernandes JG. Rational use of diagnostic tests for clinical decision making. Rev Assoc Med Bras. 2019;65(3):452-459. doi: 10.1590/1806-9282.65.3.452. R1.2: Furthermore, I wonder if Cronbach’s alfa of the items enlisted in table 2 could be summarized to recommend for future studies.Answer. Thank you for your observation. The included studies provided data to construct the 2x2 table for each short GDS version but did not provide the variance data of each short GDS version to calculate Cronbach's alpha (1). The sensitivity and specificity data did not allow us to calculate the correlation between items, hence we were unable to compute Cronbach's alpha.1. Cortina J.What is coefficient alpha: an examination of theory and applications. J Appl Psychol. 1993;78:98-104. doi: 10.1037/0021-9010.78.1.98R1.3: Line 60: it is combining? Or just selecting some items from the original 30-item version?Answer. Thank you for your observation. We have corrected the redaction of that sentence. We have changed “Therefore, shorter GDS versions, combining some of the GDS-30 items” to “Therefore, shorter GDS versions, selecting some of the GDS-30 items”.R1.4: Line 62,63: word different and altogether may not be needed.Answer. Thank you for your observation. We have changed “such as different GDS versions with four items , and different GDS versions with five items ” to “such as GDS versions with four items , and GDS versions with five items ”.R1.5: Line 147: Regarding the population, …. The sentence needs reconstruction. Only one study excluded the sample with dementia.Answer. Thank you for your observation. We have rewritten that sentence now in Line 166: “Regarding the population, one study was performed only in people without dementia [44], and the rest of the studies were performed in both groups of patients”.R1.6: Line 74-81: Authors have elaborated the various eligibility criteria for inclusion. Authors can further clarify:1. Language of the tool. If translated, whether the translation was done appropriately2. I understood that irrespective of Study design, setting, the way the interview was included. It may be better to mention.Answer. Thank you for your observation. The GDS-4 and GDS-5 versions of the included studies were translated into different languages and applied. Although it is assumed that these instruments were validated prior to their use for depression screening, there were studies that explicitly stated that they used the validated instrument, while others did not state their validation information. We included studies that evaluated the GDS-4 or GDS-5 versions independent of whether they detailed validation in the language of the study participants.Regarding the study design, we have included observational studies as those are adequately designed for the assessment of diagnostic tests. Also, we had no restrictions of setting and interview. We added the following lines in “Eligibility criteria” section Line 87-89: No restrictions on language, publication date, validation of language translation of the short GDS versions, or the mode of test assessment were applied”.In S3 Table, we added the following data: “Language of the test” and “Mode of test assessment”.R2.1: This is an interesting paper but the rationale needs to be strengthened and methods revised considerably. The methodology is presents some inaccuracies and confusion with methods used for meta-analyses of intervention reviews. I would recommend the following references to the authors;http://www.prisma-statement.org/Extensions/DTA• PRISMA for Diagnostic Test Accuracy Reviews (DTA): https://pubmed.ncbi.nlm.nih.gov/24274632/• Leeflang MM. Systematic reviews and meta-analyses of diagnostic test accuracy. Clin Microbiol Infect. 2014 Feb;20(2):105-13. doi: 10.1111/1469-0691.12474. PMID: 24274632 https://pubmed.ncbi.nlm.nih.gov/19075208/• Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM; Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med. 2008 Dec 16;149(12):889-97. doi: 10.7326/0003-4819-149-12-200812160-00008. https://methods.cochrane.org/sdt/handbook-dta-reviews• DTA meta-analyses methods: Chapter 10  of the Cochrane handbook for DTA reviews. https://gradepro.org/ GRADE Pro /GDT is a free software that enables authors conduct GRADE assessments accurately and also generates nice summary of findings tables. (Table 3 needs to follow this format)• GRADE: Answer. Thank you for your observation. We have read the suggested literature on systematic reviews and meta-analyses of diagnostic test accuracy to improve the methodology in our manuscript. We have added the following lines in the Abstract as required by PRISMA-DTA: "Study quality was assessed with the QUADAS-2 tool”, “We performed a bivariate random-effects meta-analysis to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI)", "The number of participants included was 5048", and "There was high risk of bias in the index test domain". In addition, with the corrections made in the other reviewers' comments, we comply with the rest of the content indicated in the PRISMA-DTA. In the "Material and Methods" section, we have changed "We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines" to "We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines [28]".28. McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM, Clifford T, et al. Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement. JAMA. 2018;319:388-396. doi: 10.1001/jama.2017.19163.Regarding Table 3, the Summary of Findings table format for GRADE Pro diagnostic questions does not seem to us to be the most convenient because the data on the prevalence of depression in the elderly can be very variable among different subsets of elderly people . Therefore, we opted to continue with the format of Table 3 where we place the certainty of evidence evaluated according to the GRADE methodology.1. Djernes JK. Prevalence and predictors of depression in populations of elderly: a review. Acta Psychiatr Scand. 2006;113(5):372-87. doi: 10.1111/j.1600-0447.2006.00770.x. PMID: 16603029.2. Blazer DG. Depression in late life: review and commentary. J Gerontol A Biol Sci Med Sci. 2003;58(3):249-65. doi: 10.1093/gerona/58.3.m249. PMID: 12634292.R2.2: ABSTRACTMethods section• This statement in the methods section is unclear. “We conducted sensitivity and specificity meta-analyses of those studies using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10). Do the authors mean using “Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10)” as the reference standard? In its current form, the statement implies that these were the statistical methods used to pool the estimates of sensitivity and specificity.Answer. Thank you for your observation. We meant that DSM and ICD-10 were used as reference standard. In “Methods” section of the abstract, we have changed “We conducted sensitivity and specificity meta-analyses of those studies using the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10)” to “We conducted sensitivity and specificity meta-analyses of those studies that used the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the International Classification of Diseases-10 (ICD-10) as reference standard”. R2.3: “Mostly, significant subgroup differences across versions were found”. It would be helpful to state which subgroups were measured. Do the authors means subgroup differences at different test thresholds?Answer. Thank you for your observation. We had specified which subgroups were analyzed, each subgroup is defined by a different GDS-4/-5 version and a threshold. We have added that explanation in the “Results” section of the abstract: “Mostly, significant subgroup differences at different test thresholds across versions were found”.R2.4: Conclusion• This statement in the conclusion is not qualified in the results section. “Conclusions: The accuracy of the different GDS-4 and GDS-5 versions showed a high heterogeneity”. This statement is best placed in the results section.Answer. Thank you for your observation. We added the following line in “Results” section of the abstract: “The accuracy of the different GDS-4 and GDS-5 versions showed a high heterogeneity”. In “Conclusions” section of the abstract, we added the following lines: “We found several GDS-4 and GDS-5 versions that showed great heterogeneity, mostly with a low or very low certainty of the evidence”.R2.5: MAIN TEXTIntroduction• The rationale, “accuracy remains unclear” is a vague rationale. Is the lack of clarity due to variation in accuracy estimates of existing primary studies? Please qualify that rationale better. I also disagree that the existing published systematic reviews are all outdated. Some were published in 2017 (ref 27) and 2019 (ref 26). These are recent reviews. An outdated review is usually > 5years.Answer. Thank you for your observation. We have developed the idea of our rationale as follows: Previous systematic reviews had wrongly focused their analysis, by pooling the results of different versions of each scale (GDS-4/-5) that represented different instruments as the used different questions from the GDS-30, and evaluated together the diagnostic values obtained by different scales. This analysis was incorrect as there are different types of versions of GDS-4 and GDS-5 and they should not be evaluated as one. Thus, although there are previous recent systematic reviews with metanalyses , the actual accuracy of the GDS-4/GDS-5 scales remains unclear. In “Introduction” section, we have changed “Although some previous systematic reviews have assessed this subject, these are outdated and tend to pool…” to “Although some previous systematic reviews have assessed this subject, these tend to pool…”https://doi.org/10.1016/j.archger.2019.104002.26. Krishnamoorthy Y, Rajaa S, Rehman T. Diagnostic accuracy of various forms of geriatric depression scale for screening of depression among older adults: Systematic review and meta-analysis. Archives of Gerontology and Geriatrics. 2020;87:104002. doi: 27. Tsoi KK, Chan JY, Hirai HW, Wong SY. Comparison of diagnostic performance of Two-Question Screen and 15 depression screening instruments for older adults: systematic review and meta-analysis. The British journal of psychiatry : the journal of mental science. 2017;210(4):255-60. Epub 2017/02/18. doi: 10.1192/bjp.bp.116.186932. PubMed PMID: 28209592.R2.6: It would be good to include a paragraph in the rationale about the best available test/reference test- what it is, its strengths and limitations as well as the anticipated role of the index tests. Are the GDS scales being evaluated as replacement tests for the reference tests/existing tests?Answer. Thank you for your observation. We added the following lines in “Introduction” section: “There are several scales for screening for depression among older adults, such as the Geriatric Depression Scale (GDS) [11], the Center for Epidemiologic Studies Depression Scale (CES-D), and others. However, the GDS is one of the most used to identify depression among older adults [11]. Among the strengths of the GDS, its use may be easier in people with cognitive impairment because of the simple yes-no format, and it can be used in hospital and community settings”.[11] O'Connor E, Rossom RC, Henninger M, Groom HC, Burda BU, Henderson JT, et al. U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews. Screening for Depression in Adults: An Updated Systematic Evidence Review for the US Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016.R2.7: Methods• The reporting of this review would be greatly improved if the authors were guided by the PRISMA extension for Diagnostic Test Accuracy reviews and not the original PRISMA. Please re-write this review based on PRISMA DTA.Answer. Thank you for your observation. We have added the following lines in the Abstract as required by PRISMA-DTA: "Study quality was assessed with the QUADAS-2 tool”, “We performed a bivariate random-effects meta-analysis to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI)", "The number of participants included was 5048", and "There was high risk of bias in the index test domain". In addition, with the corrections made in the other reviewers' comments, we comply with the rest of the content indicated in the PRISMA-DTA. In the "Material and Methods" section, we have changed "We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines" to "We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines [28]".28. McInnes MDF, Moher D, Thombs BD, McGrath TA, Bossuyt PM, Clifford T, et al. Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement. JAMA. 2018;319:388-396. doi: 10.1001/jama.2017.19163.R2.8: Search strategy• Please clarify why only the first 100 results yielded in google scholar were searched. Google scholar generates lots of hits. How did the authors ensure that the first 100 were the most relevant to screen?Answer. Thank you for your observation. As Google Scholar is a big and unspecific source of grey literature, which orders the results by relevance and coincidence, Systematic reviews usually examine the first results  in Google Scholar (1-3). We searched Google Scholar to identify grey literature through the first 100 records. We entered the Internet as incognito and removed the cache (data previously stored on the computer) so that previous data would have no influence on the order of appearance of the search results. These results were ordered according to relevance and were not restricted by publication date. The first 100 records were evaluated. In “Search strategy” section, we added the following lines (Line 93-100): “Google Scholar was searched to identify grey literature through the first 100 records, as systematic reviews usually examine the first 100 records in Google Scholar because it is a large and unspecific source of grey literature, which sorts results by relevance and coincidence”.1. Abdullahi A, Candan SA, Abba MA, Bello AH, Alshehri MA, Afamefuna Victor E, et al. Neurological and Musculoskeletal Features of COVID-19: A Systematic Review and Meta-Analysis. Front Neurol. 2020;11:687. doi: 10.3389/fneur.2020.006872. Joyeux L, De Bie F, Danzer E, Russo FM, Javaux A, Peralta CFA, et al. Learning curves of open and endoscopic fetal spina bifida closure: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2020;55(6):730–9. doi: 10.1002/uog.203893. Arora M, Chugh A, Jain N, Mishu M, Boeckmann M, Dahanayake S, et al. Global impact of tobacco control policies on smokeless tobacco use: a systematic review protocol. BMJ Open. 2020 Dec 24;10(12):e042860.doi: 10.1136/bmjopen-2020-042860R2.9: Data selection and extraction.• The authors state that duplicates were removed using endnote reference tool and data extraction was done using an excel sheet. Please clarify which platform/software specifically was used to screen titles, abstracts and full texts of the search yield?Answer. Thank you for your observation. Screening of titles, abstracts, and full texts was performed manually in Endnote. After eliminating duplicates, two Endnote libraries were created with the records that were found so that two people could independently perform the screening, and compare their selection of studies. We added the following lines in “Data selection and extraction” section (lines 102-104): “Two independent authors (ANF and DRSM) independently screened all results for inclusion, first reviewing the titles and abstracts, and later performing a full-text assessment, through EndNote software”.R2.10: Risk of bias and certainly of evidence• Please add more detail about how GRADE was used to assess certainty of evidence? How was downgrading done?Answer. Thank you for your observation. We added the following lines in “Risk of bias and certainty of evidence” section (Lines 125-131): “Risk of bias, indirect evidence, inconsistency, imprecision, and publication bias were assessed. We downgraded the certainty of evidence when fewer than 70% of studies had at least 7 of 10 items at low risk according to QUADAS-2, when fewer than 70% of studies had the components  similar to the initial diagnostic question, when heterogeneity was moderate or high, when the confidence interval range was greater than or equal to 10%, and when fewer than 4 studies evaluated the outcome of interest”.R2.11: Statistical analyseshttps://methods.cochrane.org/sdt/handbook-dta-reviews• This section needs to be revised for clarity. Please refer to Chapter 10  in the Cochrane handbook for DTA reviews. Answer. Thank you for your observation. The process of data analysis was performed according to the Cochrane handbook , as follows:First, we installed the package “ssc install midas” and “ssc install metaprop” in STATA, which were the packages of diagnostic and proportion meta-analysis, respectively. Then, we input the commands “midas tp fp fn tn id(author year) ms(0.75) ford fors bfor(dss)” and got the forest plots for sensitivity and specificity. When less than four studies were included for a meta-analysis, we performed meta-analyses of proportions. We input the commands “metaprop num denom, random” and got the meta-analysis of proportions. In “Statistical analyses” section, we added the following lines (Lines 137-147): “When there were at least four studies to include in the meta-analysis, we used bivariate mixed-effects models via random effects that consider the correlation between sensitivity and specificity by each study to provide estimates of effects [40]. When less than four studies were included for a meta-analysis, the mixed-effects model assessment was not appropriate, so we performed meta-analyses of proportions using the exact binomial distribution. We calculated the pooled sensitivity and specificity with their 95% confidence intervals” and “Heterogeneity was assessed through visual assessment of forest plots”R2.12: Please provide a reference to qualify the type of meta-analyses used (bivariate model). Also clarify if it was the bivariate random effects method (which is commonly used) or bivariate mixed-effects models. By mixed effects do you mean random and fixed effects combined?Answer. Thank you for your observation. We used a “bivariate mixed-effects regression framework focused on making inferences about average sensitivity and specificity” through midas command in Stata for meta-analysis for diagnostic test performance (1). This mixed model is part of the bivariate random effects method (2). We added the following line in “Statistical analyses” section (Lines 137-139): “When there were at least four studies to include in the meta-analysis, we used bivariate mixed-effects models via random effects that consider the correlation between sensitivity and specificity by each study to provide estimates of effects [43]”.http://fmwww.bc.edu/repec/bocode/m/midas.pdf1. Dwamena BA, Sylvester R, Carlos RC. MIDAS: Stata module for meta-analytical integration of diagnostic test accuracy studies. Statistical Software Components [Internet]. 2009 [cited 2021 Apr 16] Available from: 2. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58(10):982-90. doi: 10.1016/j.jclinepi.2005.02.022. PMID: 16168343.R2.13: Please state clearly at the beginning of this section that meta-analyses of GDS-4 and GDS-5 were done separatelyAnswer. Thank you for your observation. We added the following line in “Statistical analyses” section: “We performed the meta-analyses of GDS-4 and GDS-5 separately”.R2.14: Please provide a rationale why the Y index was calculated provided. This is a global measure of accuracy and to my knowledge rarely used nowadays because of its limitations.Answer. Thank you for your observation. As you rightly pointed out, the Youden index is a measure currently no longer used since it has several limitations. We found that adding the Youden index to the manuscript did not add anything new and the results were still understood despite of it. We therefore chose to delete the Youden index from the manuscript. We have removed all content about Youden Index in the "Statistical analysis", "Results", "Discussion", and "Table 3" sections.R2.15: Please revisit how heterogeneity is measured in DTA reviews. I2 is used to assess heterogeneity of intervention reviews and not recommended for DTA reviews.Answer. Thank you for your observation. We agree with you. The Cochrane Handbook for DTA reviews (1) indicates that it is not appropriate to use the i2 for sensitivity and specificity as it would overestimate the degree of heterogeneity observed. It also indicates that heterogeneity is usually assessed through visual assessment of forest plots and in ROC space. They indicate that heterogeneity can be observed through estimates with confidence intervals. When the results of the studies are different, there is little overlap in the confidence intervals. With respect to the ROC space, they indicate that it is rarely possible to obtain confidence intervals. It is impossible to assess whether the differences between studies are within the expected limit due to chance or due to real differences between studies. Therefore, we opted for the evaluation of heterogeneity through visual assessment of forest plots. We have removed the heterogeneity assessment with i2 in the manuscript and assessed heterogeneity visually with forest plots. We changed all content about I2 in the "Statistical analysis", "Results", and "Table 3" sections.https://methods.cochrane.org/sdt/handbook-dta-reviews1. DTA meta-analyses methods: Chapter 11 (Interpreting results and drawing conclusions) of the Cochrane handbook for DTA reviews. R2.16: Results• The results section about risk of bias is thin. QUADAS has four domains against which risk of bias results are reported. Please specify which domains were deemed to have risk of bias.Answer. Thank you for your observation. We added the following lines in “Results” section (Lines 199-201): “There was high risk of bias in the index test domain. Specifically, the question about the lack of pre-specification of the cut-off points was the most common flaw”.https://gradepro.org/).R2.17: Table 3. The reporting of GRADE results is incorrect. GRADE assessment is given for an overall summary of evidence and not individual studies as presented. QUADAS is for individual studies but GRADE summarises the overall certainly of evidence across the domains quality/risk of bias; inconsistency, imprecision, indirectness and publication bias. For example, one would except an overall certainly of evidence for pooled results at each cutoff but not for individual studies. Please refer to the GRADE pro software to help with the GRADE assessment as well as generation of an accurate summary of findings table .1. Guyatt GH, Oxman AD, Santesso N, Helfand M, Vist G, Kunz R, Brozek J, Norris S, Meerpohl J, Djulbegovic B, Alonso-Coello P, Post PN, Busse JW, Glasziou P, Christensen R, Schünemann HJ. GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes. J Clin Epidemiol. 2013;66(2):158-72. doi: 10.1016/j.jclinepi.2012.01.012.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 26 May 2021PONE-D-21-03547R1Accuracy of the Geriatric Depression Scale (GDS)-4 and GDS-5 for the screening of depression among older adults: a systematic review and meta-analysisPLOS ONEDear Alvaro Taype-Rondan,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.Please respond to review comments about clarifying what constitutes the overall meta-analyses versus investigations of heterogeneity in the abstract and main text (any versions vs similar versions at different common cutoff points?). In addition, do ensure that the conclusions of the review are in line with the stated objectives in both the abstract and main text.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by 26 June, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.We look forward to receiving your revised manuscript.Kind regards,Eleanor Ochodo, M.D., PhDAcademic EditorPLOS ONEJournal Requirements:Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: All comments have been addressedReviewer #2: (No Response)**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: No**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: (No Response)Reviewer #2: The authors have responded satisfactorily to the previous comments except those about thresholds.It is still unclear what the overall meta-analyses entails versus investigations of heterogeneity. Overall meta-analysis (any GDS-4 version or GDS-5 version separately at different common cutoffs? ) vs heterogeneity (same GDS version at different common cutoffs). Since different cut-offs and versions have been used it is important to be clear from the outset what constitutes the overall meta-analysis vs heterogeneity.ABSTRACT:Methods section:" We conducted sensitivity and specificity meta-analyses of those studies that used.....". Please revise to we conducted meta-analyses of the sensitivity and specificity of those studies that used......"We performed a bivariate random-effects meta-analysis to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI). " Please be very explicit what this overall meta-analyses included. For example one could rephrase as follows "we performed a bivariate random-effects meta-analysis to estimate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI) at each reported common cutoff. For the overall meta-analyses, any GDS-4 version or GDS-5 version separately, by each cut-off and for investigations of heterogeneity, across similar GDS versions by each cutoff".ResultsBeing very explicit about the cutoff and versions will help one understand the results better. For example, the first set of reported results is about all versions of GDS-4 and GDS-5 separately at cutoff>2. This implies the overall meta-analyses at cutoff 2?? and subsequent cutoffs??Conclusion:This conclusion does not accurately reflect the aim of the review which is to estimate accuracy. For example this could be reworded to " We found several GDS-4 and GDS-5 versions that showed great heterogeneity in estimates of sensitivity and specificity, mostly with a low or very low certainty of the evidence"...........MAIN TEXTStatistical analyses section page 7The overall meta-analyses vs heterogeneity is unclear. For example please see comparisons below:Lines 133-135We conducted meta-analyses of the sensitivity and specificity of GDS-4 and GDS-5 versions whenever studies fulfilled the following condition: 1) There was more than one study that compared the same version of GDS-4 or GDS-5 and used the same cut-off point.Lines 143-144In addition, we meta-analyzed all the included studies that assessed any GDS-4 version, and all the studies that assessed any GDS-5 version, by each cut-off.The first statements about meta-analyses (lines 133-135) seem similar to investigations of heterogeneity (lines 145-146).**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  11 Jun 2021Journal Requirements:1. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.Answer. Thank you for your observation. We have reviewed the list of references and made changes to the reference style to make it conform to the journal's requirements. We found that Cheng 2004 (1) and Tsoi 2017 (2) have been corrected. We added their “Erratum” information in the references (Lines 383-384 and Line 420).The list of references is complete, and no retracted studies have been cited.According to the corrected information from Cheng 2004 (1), we have changed in the column “Reference standard” of Table 1: “Major depressive disorders, dysthymia, adjustment disorder with depressed mood, dementia with depression, bipolar disorder, depressive episode assessed by DSM-III” to “Major depressive disorder, dysthymia, depressive disorder not otherwise specified, adjustment disorder with depressed mood, dementia with depression assessed by DSM-III”. This change was also made in the Supplementary File S3_Table. No other changes to the manuscript were required.1. Cheng ST, Chan AC. A brief version of the geriatric depression scale for the chinese. Psychol Assess. 2004 Jun;16(2):182-6. doi: 10.1037/1040-3590.16.2.182. Erratum in: Psychol Assess. 2006 Mar;18(1):48. PMID: 15222814.2. Tsoi KK, Chan JY, Hirai HW, Wong SY. Comparison of diagnostic performance of Two-Question Screen and 15 depression screening instruments for older adults: systematic review and meta-analysis. Br J Psychiatry. 2017;210(4):255-60. doi: 10.1192/bjp.bp.116.186932. Erratum in: Br J Psychiatry. 2017;211(2):120. pmid: 28209592.Reviewers' comments:R2.1: ABSTRACT Methods section:" We conducted sensitivity and specificity meta-analyses of those studies that used.....". Please revise to we conducted meta-analyses of the sensitivity and specificity of those studies that used......Answer. Thank you for your recommendation. We have changed in Lines 31-32: “We conducted sensitivity and specificity meta-analyses of those studies that used…” to “We conducted meta-analyses of the sensitivity and specificity of those studies that used…”.R2.2: "We performed a bivariate random-effects meta-analysis to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI). " Please be very explicit what this overall meta-analyses included. For example one could rephrase as follows "we performed a bivariate random-effects meta-analysis to estimate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI) at each reported common cutoff. For the overall meta-analyses, any GDS-4 version or GDS-5 version separately, by each cut-off and for investigations of heterogeneity, across similar GDS versions by each cutoff".Answer. Thank you for your observation. We have changed in Lines 34-39: “We performed a bivariate random-effects meta-analysis to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI)” to “We performed bivariate random-effects meta-analyses to calculate the pooled sensitivity and specificity with their 95% confidence intervals (95% CI) at each reported common cut-off. For the overall meta-analyses, we evaluated each GDS-4 version or GDS-5 version separately by each cut-off, and for investigations of heterogeneity, we assessed altogether across similar GDS versions by each cut-off”.R2.3: ResultsBeing very explicit about the cutoff and versions will help one understand the results better. For example, the first set of reported results is about all versions of GDS-4 and GDS-5 separately at cutoff>2. This implies the overall meta-analyses at cutoff 2?? and subsequent cutoffs??Answer. Thank you for your observation. The sentence implies the overall meta-analyses at cut-off 2. It does not imply subsequent cut-offs. We have changed “at a cut-off ≥ 2” to “at a cut-off 2” for better understanding.In addition, throughout the manuscript, the “≥” sign was eliminated when referring to cut-off points. For example, we have changed “cut-off ≥ 1” to “cut-off 1”.R2.4: Conclusion:This conclusion does not accurately reflect the aim of the review which is to estimate accuracy. For example this could be reworded to " We found several GDS-4 and GDS-5 versions that showed great heterogeneity in estimates of sensitivity and specificity, mostly with a low or very low certainty of the evidence"...........Answer. Thank you for your observation. We have changed in Line 51: “We found several GDS-4 and GDS-5 versions that showed great heterogeneity, mostly with a low or very low certainty of the evidence” to “We found several GDS-4 and GDS-5 versions that showed great heterogeneity in estimates of sensitivity and specificity, mostly with a low or very low certainty of the evidence”R2.5: MAIN TEXTStatistical analyses section page 7The overall meta-analyses vs heterogeneity is unclear. For example please see comparisons below:Lines 133-135We conducted meta-analyses of the sensitivity and specificity of GDS-4 and GDS-5 versions whenever studies fulfilled the following condition: 1) There was more than one study that compared the same version of GDS-4 or GDS-5 and used the same cut-off point.Lines 143-144In addition, we meta-analyzed all the included studies that assessed any GDS-4 version, and all the studies that assessed any GDS-5 version, by each cut-off.Answer. Thank you for your observation. For the overall meta-analyses, we evaluated each GDS-4 version or GDS-5 version separately by each cut-off. Regarding investigations of heterogeneity, we assessed altogether across any GDS-4 version or GDS-5 version by each cut-off. We have changed Lines 133-135 to “We conducted meta-analyses of the sensitivity and specificity of each of the GDS-4 and GDS-5 versions whenever studies fulfilled the following condition: 1) There was more than one study that compared the same version of GDS-4 or GDS-5 at the same cut-off point”.We have changed Lines 143-144 to “In addition, we meta-analyzed altogether the results of the included studies that assessed the same cut-off point of any GDS-4 version. Likewise, we meta-analyzed altogether the results of the included studies that assessed the same cut-off point of any GDS-5 version”.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 16 Jun 2021Accuracy of the Geriatric Depression Scale (GDS)-4 and GDS-5 for the screening of depression among older adults: a systematic review and meta-analysisPONE-D-21-03547R2Dear Alvaro Taype-Rondan,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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Zanthoxylum bungeanum Maxim) on the taste perception of stewed sheep tail fat. Liquid chromatography-tandem quadrupole time of flight mass spectrometry (LC-QTOF-MS) was applied to analyze the taste-related compounds. A total of 99 compounds in different sheep tail fat samples were identified. The semi-quantitative results showed that there were differences between the samples. The partial least squares discriminant analysis (PLS-DA) model without overfitting was used to investigate the effect of prickly ash. Eleven marker compounds were predicted with a variable importance for projection > 1, fold change > 2 and p < 0.05. An additional experiment showed that guanosine 5′-monophosphate, malic acid, inosine and adenosine 5′-monophosphate could improve the umami and saltiness taste of stewed sheep tail fat.This work aims to explore the contribution of prickly ash ( Sheep tail fat is an important part of the sheep with a unique flavor after heat treatment. The weight of the sheep tail fat from individual sheep varies from 3 to 8 kg. In northwest China, stewed sheep tail fat is an essential hotpot additive for many consumers to enhance its taste. However, sheep tail fat use is limited in the food industry due to its widely unaccepted flavor ,2. The lZanthoxylum bungeanum Maxim) and ginger increased the content of terpenes and cumin and amomum tsao-ko increased the content of aldehydes in the roast meat [Improving the taste of sheep tail fat is an effective way to promote its industrial development and solve the extrusion problem of sheep tail fat. Spices have a long planting history in China and they have been widely used in meat product processing because of their seasoning, flavoring, appetizing and other functions ,4. Gourmast meat . Althougast meat . The addast meat .In order to fully understand the flavor characteristics of the research sample, a greater number of compounds need to be identified for the subsequent analysis. Mass spectrometry has been widely used in food flavor analyses due to its high-resolution ratio and sensitivity . A largep < 0.05. The taste characteristics of the marker compounds were verified by an additional experiment and an electronic tongue.In this work, prickly ash-processed stewed sheep tail fat and stewed sheep tail fat were used as the main research samples to explore the effect of prickly ash on the taste contribution to the sheep tail fat. The compounds in all samples were identified by liquid chromatography-tandem quadrupole time of flight mass spectrometry (LC-QTOF-MS/MS) and the compounds were semi-quantified by internal standard compounds. A reliable PLS-DA model was established based on a permutation test and cross-validation and marker compounds were selected through variable importance in projection (VIP) > 1, fold change (FC) > 2 and Sheep tail fat (Sunit sheep) and prickly ash (powder) were purchased from Xilingol League, Inner Mongolia and Guangxi province, respectively. Methanol with an MS grade was purchased from Merck Chemical Technology Co. Ltd. . Ammonium formate and formic acid with an MS grade were purchased from Bailingwei Technology Co. Ltd. . Ultrapure water was purchased from Watson’s food and beverage Co. Ltd. ; flavone, L-theanine, 1,2-dichlorobenzene, methyl palmitate, silibinin and gamma-nonanolactone with an analytical grade were all purchased from Aladdin biochemical technology Co. Ltd.  and guanosine 5′-monophosphate (5′-GMP), malic acid, inosine, adenosine 5′-monophosphate (5′-AMP), guanosine, fumaric acid and 18β-glycyrrhetinic acid with an analytical grade were purchased from Sigma-Aldrich .According to the pre-experiment results in our group, the optimal technology of stewing sheep tail fat was a solid–liquid ratio of 1:2 and a stewing time of 3 h. Therefore, to explore the effect of prickly ash on stewed sheep tail fat, stewed sheep tail fat with 0.2% prickly ash (SP) was studied; stewed sheep tail fat (S) and stewed prickly ash (P) served as the controls. Each sample was repeated three times.After stewing, the fat blocks and the liquids were separated with gauze then the liquids were transferred to the separating funnel. The water phase and the oil phase were then separated and finally we obtained three parts: soup (OP); the fat block (OB); and the upper oil layer (OU). The fat block was placed in a beaker, mixed with 50% edible alcohol in the ratio of 1:1 and ultrasonicated for 30 min at 400 W. After ultrasonic treatment, it was filtered with gauze and the filtrated liquid was transferred into a separating funnel. After the separation, the water phase was collected to obtain the sample. The upper oil layer was placed in a beaker, mixed with 50% edible alcohol at a ratio of 1:1 and ultrasonicated for 15 min at 400 W. After ultrasonic treatment, this was filtered with gauze and the filtrated liquid was transferred into a separating funnel. After the separation, the water phase was collected to obtain the sample. Finally, we obtained three group of samples: soups ; fat blocks ; and an upper oil layer .The panelists of sensory evaluation were recruited from the laboratory and received systematic taste training. Panelists who could distinguish five basic tastes were selected. A total of 12 panelists  were selected to evaluate the samples. According to previous results ,16,17, tIn order to explore the contribution of prickly ash to the taste of stewed sheep tail fat, S, P and SP samples  were simultaneous presented to the panelists to evaluate the taste profiles in the sensory evaluation laboratory . The three samples were coded with three digital numbers and were submitted to the panelists for sensory evaluation in a random order. The panelists scored the five basic taste intensities by referencing the standard reference compounds. The overall taste was evaluated according to the preference of the panelists. Each sample was repeated three times.An electronic tongue  was used to analyze the taste characteristics including umami, sweetness, saltiness, sourness and bitterness. The sensors were soaked in a reference solution (30 mM KCl solution with 0.3 mm tartaric acid) for more than 24 h including AAE (umami), GL1 (sweetness), CT0 , CA0 (sourness) and C00 (bitterness) coupled to a reference electrode (Ag/AgCl). Before the determination, the instrument was calibrated and initialized to ensure the stability and reliability of the data. The injection procedure was set as the sample taste collection time (30 s) and the cleaning time (300 s). Each sample was repeated three times.® C18 column  with a flow rate of 0.6 mL/min, an injection volume of 10 μL and a column temperature of 40 °C in both ESI+ and ESI− modes. For ESI+, the mobile phase consisted of A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile); for ESI−, the mobile phase consisted of A (20 mM ammonium formate in water) and B (0.1% formic acid in acetonitrile). A gradient elution was carried out using 0–33.0 min, 5–18% B; 33.1–46.0 min, 35% B; 46.1–49.0 min, 80% B; 49.1–53.0 min, 80% B; 53.1–54.0 min, 95% B; and 54.1–60.0 min, 5% B.The compound analysis was performed on a UPLC-ESI-QTOF system . Chromatography separation was achieved on a Kinetexm/z 50–1000. A dynamic background subtraction (DBS) trigger information-dependent acquisition (IDA) was used to obtain the MS/MS data. The maximum candidate ion number of 15 was selected and the intensity threshold was set as 100 cps. The electrospray ion source temperature and the spray voltage were set to 550 °C, 5500 V and 550 °C, −4500 V for the ESI+ and ESI− modes, respectively. The declustering potential (DP), collision energy (CE), collision energy spread (CES), gas 1, gas 2 and curtain gas were 80 V, 35 V, ±15 V, 55 psi, 60 psi and 35 psi, respectively. A continuous recalibration was carried out after every ten samples with CDS tuning fluid and one quality control (QC) sample  was inserted for every five samples. The accurate mass and composition of the precursor ions and fragment ions were obtained. The compounds was analyzed by the MassBank database (https://massbank.eu/MassBank/ (accessed on 20 August 2021)) and subsequently ensured by an ion fragment from the standard compounds.The mass spectrometric data were collected on a SCIEX X500R QTOF mass spectrometer . The TOF-MS and TOF-MS/MS were scanned with a mass range of + mode, others can only be detected in the ESI− mode and a few compounds can be detected in both ESI+ and ESI− modes. To facilitate the subsequent data analysis, the identified compounds were semi-quantified and six compounds were selected as the internal standards: flavone; L-theanine; 1,2-dichlorobenzene; methyl palmitate; silibinin; and gamma-nonanolactone. The semi-quantitative compounds by different internal standards are shown in When considering the different properties of the compounds, it should be noted that a few compounds can only be detected in the ESIAccording to the analysis results of the PLS-DA, the marker compounds of the three group samples  were selected. In addition, 7 compounds were selected for a subsequent analysis that might contribute to taste according to previous works ,18. The https://www.metaboanalyst.ca/ (accessed on 7 September 2021)) was uploaded. Subsequently, the data were pre-processed including the estimate missing value (KNN), the normalized by mean-centered and the pareto-scaled data. The PLS-DA model was used to select the metabolites and separate the groups  with the parameter of VIP > 1, FC > 2 and p < 0.05. A cross-validation (R2 and Q2) was used to verify the stability of the model and a permutation test (1000 cycles) was used to prove that the model was not overfitting [Before performing the multivariate statistical analysis, a semi-quantitative data file to MetaboAnalyst 4.0 ).The mass spectrometry data acquisition and processing were based on SCIEX OS software 1.5 . A statistical analysis of the electronic tongue data was performed using Microsoft Excel. The PCA and PLS-DA models were carried out by MetaboAnalyst (R = 0.98). The bitterness value was also significantly related to the content of bitter amino acids (R = 0.96) [The results of the sensory evaluation are shown in  = 0.96) . Therefo+ and ESI−) were identified including amino acids (14), nucleotides (17), organic acids (16), sugars (3), peptides (2), fatty acids (6), flavonoids (10) and others (31)  . In ordeers (31) , which sR2 = 0.997, Q2 = 0.984) obtained can be seen in R2 and Q2 were ≥ 0.5, suggesting that the model was stable and reliable [p < 0.05, as summarized in According to the semi-quantitative results, a PLS-DA model was established to select the marker compounds taking the soup samples as an example . In thisreliable . The perSalvia miltiorrhiza Bunge during the predation process and the production of tanshinone IIA through the catabolism in vivo that has not been completely metabolized. However, up to the present time, there is no literature on its taste characteristics, only studies on its anti-tumor effect [Three marker compounds were selected in the soup samples; 5′-GMP, malic acid and tanshinone IIA . 5′-GMP r effect . TherefoThree marker compounds were selected from the fat block samples after stewing; guanosine, 5′-AMP and inosine . NucleosN-heptylfuran . This work mainly focused on the taste compounds; that is, non-volatile water-soluble compounds. The two compounds were, therefore, not discussed in detail although they were detected through the LC-MS system. 18β-glycyrrhetinic acid mainly comes from licorice but it has been detected in sheep tail fat. This may be because sheep can feed on licorice and the glycyrrhizic acid in licorice degrades into 18β-glycyrrhetinic acid in the sheep body. He et al. found certain residues in different tissues of rats fed with nutritious soup, which further verified the factual basis for the detection of 18β-glycyrrhetinic acid in sheep tail fat [A total of five compounds were selected in the upper oil layers samples; stearic acid, fumaric acid, 18β-glycyrrhetinic acid, methyl jasmonatepure and 2-tylfuran . Stearictail fat . As a swtail fat .p < 0.05) [The above analysis indicated the addition of prickly ash promoted the release of a few compounds. This might have been due to the presence of these compounds in prickly ash or the interaction during the stewing process that promoted the release of these compounds. Yu et al. studied the effect of natural spices on the flavor substances of stewed Wuding chicken. The results showed that the content of the total fatty acids, water-soluble small molecular weight compounds and volatile flavor substances in the treatment group was significantly higher than that in the control group ( < 0.05) . It coulThrough the analysis of the marker compounds and combined with the results reported in the previous literature, 7 compounds (nucleotides and organic acids) were selected, which were 5′-GMP and malic acid in the OP samples; inosine, 5′-AMP and guanosine in the OB samples; and fumaric acid and 18β-glycyrrhetinic acid in the OU samples.p < 0.05). 18β-glycyrrhetinic acid has been reported as having a strong sweetness taste [The electronic tongue analysis results of the seven compounds are shown in ss taste  but it wAn additional test was used to verify the taste effect of the compounds in stewed sheep tail fat. Seven compounds were added to the S-OP sample individually to explore the taste contribution. The analysis results of the electronic tongue are shown in A total of 99 compounds were detected in stewed sheep tail fat samples by LC-QTOF-MS/MS. The semi-quantitative results showed that the addition of prickly ash resulted in a difference of the compounds in sheep tail fat. A PLS-DA was performed to predict 11 marker compounds associated with the taste of stewed sheep tail fat. An additional experiment was conducted to explore the taste contribution of compounds (three organic acids and four nucleotides) to stewed sheep tail fat. The electronic tongue results showed that 5′-GMP, malic acid, inosine and 5′-AMP had a taste effect on stewed sheep tail fat, which improved the umami and saltiness taste and reduced the bitterness taste. This work confirmed the contribution of prickly ash to the taste effect of stewed sheep tail fat and provides theoretical guidance for the processing of sheep tail fat.